Thymidylate synthase

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spinqualitylabelsall models Thymidylate synthase complex with dUMP (PDB entry 1tsv) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 Function 2 Relevance 3 Structural highlights 4 3D structures of thymidylate synthase Function Thymidylate synthase (TS) catalyzes the methylation of dUMP to dTMP using 5,10-methylenetetrahydrofolate as a cofactor. TS is essential for DNA replication and repair[1]. In protozoa, dihydrofolate reductase (DHFR) and TS are expressed as a bifunctional monomeric enzyme (DHFR-TS) with the DHFR entity at the N terminal. DHFR and TS catalyze consecutive reactions in the dTMP biosynthesis. There are two different types of TS – ThyA and ThyX. The types differ in their activity and structure. The TS ThyX are flavin-dependent enzymes. Relevance TS inhibition at its folate-binding site is used in anticancer therapeutic drugs. DHFR-TS inhibitors are potential drug targets against parasite-transferred diseases. TS exhibits oncogene-like activity.[2] Structural highlights TS [3]. Water molecules are shown as red spheres. 3D structures of thymidylate synthase Thymidylate synthase 3D structures

3D structures of thymidylate synthase

Updated on 26-February-2020 {{#tree:id=OrganizedByTopic|openlevels=0|

• Thymidylate synthase

• • 1hw3, 1hw4, 1hzw, 1ypv, 2onb, 4gyh, 4h1i, 4up1, 5x5a, 5x693n5g, 4kpw - hTS – human
    
  • 2rd8, 2rda, 3egy, 3ehi, 3eaw, 3ebu, 3ed7, 3edw, 3ef9, 3ejl, 3gg5, 3gh0, 3gh2, 4jef, 4o1u, 4o1x, 5x4w, 5x4x, 5x4y, 6qyq – hTS (mutant)
    
  • 3ihi, 6qyj – mTS – mouse
    
  • 4iqb – nTS – nematode
    
  • 3tms, 1tjs, 1f4b, 2ftq – EcTS – Escherichia coli
    
  • 1ajm, 1bq2, 1qqq, 1ev5, 1ev8, 1evf, 1evg, 1ffl, 2g8x, 2ftn - EcTS (mutant)
    
  • 4tms, 1tda - LcTS – Lactobacillus casei
    
  • 1tsw, 1tsz - LcTS (mutant)
    
  • 1tis – TS – Enterobacteria phage T4
    
  • 1bsf, 1bko, 1bkp, 1bsp - BsTS - Bacillus subtilis
    
  • 3ix6 – BmTS – Brucella melitensis
    
  • 3kgb – TS – Encephalitozoon cuniculi
    
  • 3v8h – TS – Burkholderia thailandensis
    
  • 4h0r - CgTS – Corynebacterium glutamicum
    
  • 4xse - VvTS – Varicella-zoster virus
    
  • 6auj - TS – Elizabethkingia anophelis
    

• Thymidylate synthase binary complex

• • 6qsh - hTS + dUMP
    
  • 3hb8 - hTS (mutant) + UMP
  • 6qxg - hTS + fluoro-dUMP
    
  • 3h9k - hTS (mutant) + fluoro-dUMP
  • 5wrn - hTS + CMP
    
  • 3ob7 - hTS (mutant) + glutathione
    
  • 4g2o – hTS (mutant) + purpurogallin
    
  • 4gd7 – hTS + purpurogallin
    
  • 4g6w – hTS (mutant) + bromobenzine-triol
    
  • 3n5e, 4fgt - hTS + peptide inhibitor
    
  • 4e28 - hTS + inhibitor
    
  • 6r2e – hTS (mutant) + folate derivative
    
  • 4e5o - mTS + UMP
    
  • 4ein – mTS + substrate analog
    
  • 4ez8 – mTS + substrate analog + dihydrofolate
    
  • 4psg – nTS + inhibitor
    
  • 4irr, 4isw – nTS + UMP
    
  • 5by6 – TwTS + UMP – Trichina worm
    
  • 1tmk - TS + TMP – yeast
    
  • 1tdc, 1thy, 2tdm, 5x5d – LcTS + UMP
    
  • 1tsv, 1tsx, 1tsy, 1njd, 1njb, 1vza, 1vzb, 1jmf, 1jmg, 1jmh, 1jmi, 1bo7, 1bo8, 1bp6, 1bpj, 1bp0, 2g86, 2g89, 2g8a, 2g8d - LcTS (mutant) + UMP
    
  • 1vzc - LcTS (mutant) + fluoro-UMP
    
  • 1nja, 1njc - LcTS (mutant) + CMP
    
  • 1nje - LcTS + CMP
    
  • 1tdb - LcTS + fluoro-UMP
    
  • 1tsl, 1tsm - LcTS + inhibitor
    
  • 4tmk, 5tmp - EcTS + inhibitor
    
  • 1an5 - EcTS + inhibitor
    
  • 1fwm - EcTS (mutant) + inhibitor
    
  • 1bid - EcTS + UMP
    
  • 1aob, 1bdu - EcTS + deoxyuridine derivative
    
  • 1f4c, 1f4e - EcTS + tosyl-proline derivative
    
  • 1f4d - EcTS (mutant) + tosyl-proline derivative
    
  • 1f4f, 1f4g - EcTS + glutamyl-proline derivative
    
  • 2vet - EcTS (mutant) + UMP
    
  • 3b9h - EcTS + nitro-UMP
    
  • 3bfi - EcTS (mutant) + nitro-UMP
    
  • 4dq1 - TS + UMP – Staphylococcus aureus
    
  • 3uwl – EfTS + 5-formyl tetrahydrofolate – Enterococcus faecalis
    
  • 6qya – EfTS + dUMP
    
  • 5j7w – EfTS + drug
    
  • 4foa - MtTS + fluoro-UMP – Mycobacterium tuberculosis
    
  • 4h0u – CgTS + UMP
    
  • 4xsc - VvTS + d-Uridine derivative
    
  • 4xsd - VvTS + dUMP
    

• Thymidylate synthase ternary complex

• • 1hvy, 1i00, 5x5q, 5x66, 5x67 - hTS + drug + UMP
    
  • 1e2d, 1e2e, 1e2f - hTS (mutant) + ADP + TMP
    
  • 5hs3, 6pf6, 6pf5, 6pf4, 6pf3, 6ojv, 6oju - hTS + inhibitor + dUMP
    
  • 1ju6, 1juj - hTS (mutant) + inhibitor + UMP
    
  • 5fct - mTS + inhibitor + fluoro-UMP
    
  • [[4eb4 - mTS + drug + UMP
    
  • 6f6z - mTS + folate derivative + CMP derivative
    
  • 1rts, 2tsr - TS + drug + UMP – rat
    
  • 4iqq – nTS + UMP + drug
    
  • 5noo - TS + drug + UMP – Caenorhabditis elegans
    
  • 5m4z - TwTS + folate derivative + CMP derivative
    
  • 2tdd - LcTS + inhibitor+ fluoro-UMP
    
  • 1vzd - LcTS (mutant) + inhibitor+ fluoro-UMP
    
  • 1vze, 1tvu, 1tvv, 1tvw - LcTS (mutant) + inhibitor+ UMP
    
  • 1lca, 1lce, 3bnz - LcTS + inhibitor+ UMP
    
  • 1lcb - LcTS + inhibitor+ TMP
    
  • 3byx, 3bz0, 3c06, 3c0a, 3ijz, 3ik0, 3ik1 - LcTS + phthalimidic derivative + UMP
    
  • 1tys - EcTS + inhibitor+ TMP
    
  • 2fto, 3bgx - EcTS (mutant) + inhibitor+ TMP
    
  • 1tlc - EcTS + inhibitor+ GMP
    
  • 1syn, 1tsd - EcTS + inhibitor+ UMP
    
  • 2bbq, 2tsc, 1kce, 1trg, 1kzi, 4isk, 4lrr - EcTS + inhibitor+ UMP
    
  • 1zpr, 1aiq, 1dna, 1bq1, 1kzj, 2vf0, 3b5b - EcTS (mutant) + inhibitor+ UMP
    
  • 1tls, 1tsn - EcTS + inhibitor+ fluoro-UMP
    
  • 3bhl, 3bhr - EcTS + inhibitor+ nitro-UMP
    
  • 1bjg - EcTS (mutant) + inhibitor+ fluoro-UMP
    
  • 2kce, 1axw - EcTS + drug + UMP
    
  • 1jtq, 1jtu, 1jut, 1jg0, 2a9w - EcTS + inhibitor+ UMP
    
  • 1nce - EcTS (mutant) + inhibitor+ UMP
    
  • 1ddu, 1tdu - EcTS + deoxyuridine derivative + inhibitor
    
  • 6cdz - EcTS + deoxyuridine + UMP
    
  • 4gev - EcTS + deoxyuridine derivative + cofactor analog
    
  • 6nnr - EcTS + deoxyuridine derivative + folate derivative
    
  • 1b02 - BsTS + inhibitor+ fluoro-UMP
    
  • 1ci7 - PcTS + inhibitor+ UMP – Pneumocystis carinii
    
  • 1f28 - PcTS + inhibitor+ UMP
    
  • 2aaz - TS + inhibitor+ UMP – Filobasidiella neoformans
    
  • 3qj7 - MtTS + spermine + UMP
    
  • 4fog - MtTS + fluoro-UMP + methy-DHF
    
  • 4fox, 4fqs - MtTS + inhibitor + fluoro-UMP
    
  • 4o7u - EfTS + phthalimidic derivative + folate derivative
    
  • 6qxs - EfTS + fluoro-dUMP + folate derivative
    

• Bifunctional dihydrofolate reductase-thymidylate synthase see Dihydrofolate reductase

• Flavin-dependent thymidylate synthase ThyX

• • 2af6, 3gwc - MtTS + FAD + halo-UMP
    
  • 3hzg - MtTS + FAD
    
  • 2gq2 - MtTS (mutant) + NADP
    
  • 2cfa - TS + FAD – Paramecium bursaria chlorella virus
    
  • 5jfe - TmTS + FAD + UMP – Thermotoga maritima
    
  • 3g4a, 3g4c, 3n0b, 3n0c - TS (mutant) + FAD + UMP
    
  • 1o24 – TmTS
    
  • 1o25 – TmTS + UMP
    
  • 1o2a – TmTS + FAD
    
  • 4gtc, 4gtl, 4kar – TmTS (mutant) + FAD
    
  • 1o26 – TmTS + FAD + UMP
    
  • 4gtd, 4kas, 4kat, 5iot – TmTS (mutant) + FAD + UMP
    
  • 1o27, 1o28, 1o29 – TmTS + FAD + halo-UMP
    
  • 1o2b – TmTS + FAD + phosphate
    
  • 4gta – TmTS + FAD + UMP + folate derivative
    
  • 4gt9 – TmTS + FAD + UMP + folate
    
  • 4gtf – TmTS (mutant) + FAD + UMP + folate
    
  • 4gte – TmTS (mutant) + FAD + folate
    
  • 4gtb – TmTS + FAD + UMP + drug
    
  • 5chp – TmTS + FAD + UMP + inhibitor
    
  • 5ioq, 5ior – TmTS + FAD + d-Uridine derivative
    
  • 5ios, 2iot – TmTS (mutant) + FAD + dUMP
    
  • 3ge9 - CgTS
    
  • 3fnn - CgTS + FAD
    
  • 3ah5, 3n3y - TS + FAD + UMP – Helicobacter pylori
    
  • 4p5a, 4p5b – TS + FAD + dUMP derivative – Streptomyces cacaoi
    
  • 6j61 - TS + FAD – Thermus thermophilus
    

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References

1. ↑ Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, Ayusawa D. Structural and functional analysis of the human thymidylate synthase gene. J Biol Chem. 1990 Nov 25;265(33):20277-84. PMID:2243092
2. ↑ Rahman L, Voeller D, Rahman M, Lipkowitz S, Allegra C, Barrett JC, Kaye FJ, Zajac-Kaye M. Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme. Cancer Cell. 2004 Apr;5(4):341-51. PMID:15093541
3. ↑ Finer-Moore JS, Fauman EB, Morse RJ, Santi DV, Stroud RM. Contribution of a salt bridge to binding affinity and dUMP orientation to catalytic rate: mutation of a substrate-binding arginine in thymidylate synthase. Protein Eng. 1996 Jan;9(1):69-75. PMID:9053905